Mitogen-activated protein kinases (MAPKs) are a highly conserved family of protein serine/ threonine kinases involved in signal transduction pathways in yeast, flies, and mammals, and are activated in response to a variety of signals. In mammals, MARK proteins p42/p44 (also called ERK 1/2) phosphorylate and activate a number of targets in both the cytoplasm and the nucleus, and in cell culture systems, a strong correlation exists between the subcellular localization of MAPK and the subsequent cellular responses elicited. However, preliminary data from our lab suggests that MAPK can function to promote cell proliferation after translocation to the nucleus even when it does not become phosphorylated. I therefore plan to test this suggestion directly, with the following two specific aims: 1) Is MAPK phosphorylation required for MAPK nuclear translocation and cell cycle progression?, and 2) What are the factors mediating MAPK hold in the cyoplasm vs. translocation to the nucleus in cell cycle regulation? As alterations in the Ras/MAPK pathway are associated with approximately 25% of human tumors, a deeper understanding of how MAPK nuclear translocation affects this process could enhance our understanding of human cancers.